Creatine oral supplementation using creatine hydrochloride salt

ABSTRACT

The present invention is directed to an oral supplement including creatine hydrochloride, which has an aqueous solubility that is at least 15 times greater than creatine monohydrate, where the oral supplement drives significant improvements in muscle development and recovery due to its enhanced bio-availability, while causing fewer negative side effects compared to previous forms of creatine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 14/629,532,filed Feb. 24, 2015, now U.S. Pat. No. 9,486,424, which is acontinuation of U.S. patent application Ser. No. 13/740,909, filed Jan.14, 2013, now U.S. Pat. No. 8,962,685, which is a divisional of U.S.patent application Ser. No. 12/909,377, filed Oct. 21, 2010, now U.S.Pat. No. 8,354,450, which is a continuation-in-part of U.S. patentapplication Ser. No. 12/477,413, filed Jun. 3, 2009, now U.S. Pat. No.8,026,385, which is a continuation of U.S. patent application Ser. No.10/846,782, filed May 14, 2004, now U.S. Pat. No. 7,608,641, whichclaims priority to U.S. Provisional Application 60/470,356, filed May15, 2003, the entirety of which is incorporated herein.

FIELD OF THE INVENTION

The present invention is directed to a form of creatine that hasincreased aqueous solubility, increased plasma uptake at low dosageamounts, and improved stability and half-life. In particular, thepresent invention relates to a creatine supplement that, when comparedto creatine monohydrate, has an increased aqueous solubility of at leastan order of magnitude, a bioavailability or plasma uptake level of atleast 50 percent greater than creatine monohydrate, and a shelf-life ofmore than double the shelf-life of creatine monohydrate.

BACKGROUND OF THE INVENTION

Creatine is a naturally occurring nitrogenous compound found in theskeletal muscles of vertebrates that plays an important role in proteinmetabolism and other bio-chemical functions. For example, creatine istaken up into muscle cells by specific receptors and converted tophosphocreatine by creatine kinase.

Both creatine and phosphocreatine play an important role in theanaerobic production of ATP during short and intensive exertions, viathe creatine kinase system. Specifically, during muscle contraction,there is an increase in the amount of phosphocreatine (which isgenerated from creatine) and consequently in ATP. The amount ofphosphocreatine in the muscle cell determines the amount of time ittakes for a muscle to recover from activity; thus, supplementing thediet with creatine can increase the concentration of phosphocreatine inmuscles by 6 percent to 16 percent, with a consequent increase in theATP turnover during physical exertion.

Creatine-containing supplements have been shown to increase lean bodymass, high intensity power output, and overall physical strength. Byvirtue of these characteristics, creatine has met with enormous successamong professional and recreational athletes, as well as professionaland amateur bodybuilders, in recent years as a dietary supplement.

Increasing creatine levels in muscle through dietary supplementation hasproven effective at enhancing athletic performance, increasing muscleworkload and shortening muscle recovery time. In addition, there isincreasing interest in creatine dietary supplements for a variety oftherapeutic indications, including muscular dystrophy, cardiovasculardiseases, neurodegenerative disorders, and mental retardation. Thezwitterionic creatine monohydrate has been the standard creatine salt ofchoice for commercial creatine supplement formulations.

However, creatine supplements containing creatine monohydrate are notideal dietary supplements due to their low aqueous solubility. In otherwords, relatively large doses of creatine monohydrate must be consumedwith large amounts of fluid for effective use. People often experienceexcessive water retention (bloating), cramps, and significantgastrointestinal problems due to the large dosages. In addition, therelatively high doses of creatine monohydrate required to produce thedesired biological effects suggest that the oral bioavailability ofcreatine monohydrate is low and that more efficient dosage forms mayprovide better desired results accompanied by fewer gastrointestinalside effects.

There are other known salt forms of creatine including creatine citrate(creatine effervescent) and creatine pyruvate that have been patentedand marketed as improvements over creatine monohydrate. However, despitethe various salt forms currently marketed, there remains a need in theart for a more improved form of creatine with improved solubility andbioavailability characteristics that can be consumed in smaller dosageforms.

SUMMARY OF THE INVENTION

The present invention is directed to a supplement that includes creatineHCl, wherein the creatine HCl possesses a solubility of at least 600mg/mL in water at 25° C. In one embodiment, the creatine HCl is at least95 percent free of contaminants. In another embodiment, the recommendeddosage range for the creatine HCl is between about one quarter teaspoonto about one tablespoon per hundred pounds body weight.

In this aspect of the invention, the supplement may be being takenorally. In one embodiment, the creatine HCl has a shelf-life of at leastabout 45 days in aqueous solution at room temperature. In anotherembodiment, an effective dosage of the supplement is about 500 mg toabout 1500 mg of creatine HCl per 100 pounds body weight. In yet anotherembodiment, the creatine HCl further comprises an additive or feedsupplement for livestock.

The present invention is also directed to a formula used to enhanceathletic performance including creatine HCl, wherein the creatine HClexhibits an aqueous solubility that is at least about 15 times greaterthan that of creatine monohydrate. In one embodiment, the formula alsoincludes additional species of creatine selected from the groupcomprising creatine esters, creatine pyruvate, creatine phosphate,creatine alpha-ketoglutarate, creatine citrate, and combinationsthereof. In another embodiment, the formula also includes additionalsupplements selected from the group comprising carbonate salts,methylsulfonylmethane, glucosamine, and chondroitin.

In yet another embodiment, the formula also includes compounds selectedfrom the group comprising proteins, amino acid supplements,carbohydrates, D-Ribose, fats, fiber and combinations thereof. In stillanother embodiment, the formula also includes sweeteners selected fromthe group comprising sucralose, aspartame, saccharin, acesulfamepotassium, neohesperidin dihydrochalcone, glycyrrhizin, thaumatin,alitame, stevioside, and combinations thereof. In one embodiment, theformula further includes a supplement selected from the group comprisingsports bars, nutritional bars, powders, liquids, gels, sports drinks,and beverages. In another embodiment, the formula also includesflavoring agents selected from the group comprising cocoa, yogurt,peanut butter, mint, cheesecake, hazelnut paste, almonds, granola,coconut, strawberry, banana, cherry, plum, raspberry, lemon, orange,lime, pineapple, blueberry and other fruit flavors, coffee, or cremesand jellies, and combinations thereof.

The present invention is also directed to a granular powder including acreatine HCl product formed by the reaction of an alcohol, an acidcatalyst, and creatine monohydrate, wherein the solubility of thecreatine HCl product is at least about 650 mg/ml.

In this aspect of the invention, the alcohol may be selected from thegroup consisting of ethanol, methanol, butanol, and isopropanol. In oneembodiment, the reaction is a super-saturated reaction includingethanol, acetyl chloride, and creatine monohydrate. In one embodiment,the volume of ethanol used is between about 4 and 5 L per kg of creatinemonohydrate and the quantity of acetyl chloride used is between about1.0 to about 1.1 mole equivalents of creatine monohydrate.

In another embodiment, the super-saturated reaction further includes thesteps of mixing the alcohol and acetyl chloride in a reactor that iscooled to between about 0° C. and 20° C.; allowing the temperature ofthe reactor to increase to about 38° C.; adding creatine monohydrate;and maintaining a temperature of between about 30° C. and about 40° C.The creatine HCl product is preferably at least 95 percent free ofcontaminants.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the invention can be ascertained fromthe following detailed description that is provided in connection withthe drawing(s) described below:

FIG. 1 is a graphical representation in linear form of the stability ofcreatine HCl in aqueous solution as compared to creatine monohydrate;and

FIG. 2 is a graphical representation in log form of the stability ofcreatine HCl in aqueous solution as compared to creatine monohydrate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a third generation form ofcreatine, specifically a creatine hydrochloride salt (“creatine HCl”)that has improved aqueous solubility, plasma uptake, and shelf-life overthat of previous forms of creatine. The present invention furthercontemplates suitable methods to produce the creatine HCl in a granularprecipitate form with high purity and yield.

The creatine HCl of the present invention may be used as a nutritionalsupplement for enhancing muscle performance and muscle mass in bothhumans and livestock, including muscle quality in livestock. In thisregard, based on the known beneficial qualities of creatine with regardto muscle development and recovery, it is believed that the improvementsin solubility and plasma uptake of the creatine HCl of the presentinvention also lead to significant improvements in muscle developmentand recovery as compared to creatine monohydrate. Moreover, withoutbeing bound to any particular theory, the improvements in the solubilityand plasma uptake also reduce or essentially eliminate the negative sideeffects typically associated with previous forms of creatine.

Creatine HCl Solubility

The creatine HCl of the present invention represents an improvement onprior forms of creatine due to is its remarkably high aqueoussolubility. As the low oral absorption of creatine supplements arebelieved to be attributable at least in part to reduced solubility, thecreatine HCl of the present invention is also expected to have betteroral absorption properties compared to other forms of creatine.

The creatine HCl of the invention preferably has an aqueous solubilityof at least about 150 mg/ml at room temperature. In one embodiment, thecreatine HCl preferably possesses an aqueous solubility at roomtemperature of about 240 mg/mL or greater, more preferably of about 480mg/mL or greater, and more preferably of about 800 mg/mL or greater. Inanother embodiment, the aqueous solubility of the creatine HCl of theinvention ranges from about 250 mg/ml to about 1000 mg/ml. In yetanother embodiment, the creatine HCl has an aqueous solubility of about400 mg/ml to about 1000 mg/ml. In still another embodiment, the aqueoussolubility of the creatine HCl of the invention is at least about 650mg/ml, preferably at least about 675 mg/ml. For example, the aqueoussolubility of the creatine HCl is preferably 679±18 mg/ml when tested atroom temperature (25° C.) after a time period of about 1.5 hours.

In comparison, the aqueous solubility of other forms of creatineincluding creatine monohydrate and creatine citrate salt typicallyranges from about 10 to about 16 mg/mL. Accordingly, the creatine HCl ofthe present invention exhibits an aqueous solubility that is at leastabout 15 times greater than that of creatine monohydrate. In oneembodiment, the aqueous solubility of the creatine HCl is at least about20 times greater than that of creatine monohydrate, preferably at leastabout 30 times greater than that of creatine monohydrate. In anotherembodiment, the creatine HCl has an aqueous solubility that is at leastabout 40 times greater than that of creatine monohydrate, preferably atleast about 50 times greater than that of creatine monohydrate. Forexample, the aqueous solubility of the creatine HCl is preferably 42times greater than that of creatine monohydrate when tested at roomtemperature (25° C.) after a time period of about 1.5 hours.

Creatine HCl Bioavailability

The creatine HCl of the present invention exhibits improvedbioavailability compared to creatine monohydrate. As used herein, theterm “bioavailability” refers to the rate and amount of a drug (or inthis case a supplement) that reaches the systemic circulation of apatient following administration of the drug or prodrug thereof to thepatient. Accordingly, bioavailability is one of the principalpharmacokinetic properties of drugs and can be determined by evaluating,for example, the plasma or blood concentration-versus-time profile for adrug. Parameters useful in characterizing a plasma or bloodconcentration-versus-time curve include the area under the curve (AUC),the maximum drug concentration (C_(max)), and the time to maximumconcentration (T_(max)).

As used herein, the term “AUC” refers to the area under a curverepresenting the concentration of a compound or metabolite thereof in abiological fluid, e.g., plasma and blood, in a patient as a function oftime following administration of the compound to the patient. The AUCmay be determined by measuring the concentration of a compound ormetabolite thereof in a biological fluid using methods such as liquidchromatography-tandem mass spectrometry (LC/MS/MS), at various timeintervals, and calculating the area under the plasmaconcentration-versus-time curve. Suitable methods for calculating theAUC from a drug concentration-versus-time curve are well known in theart.

C_(max) is the maximum concentration of a drug in the plasma or blood ofa patient following administration of a dose of the drug or form of drugto the patient. T_(max) is the time to the maximum concentration(C_(max)) of a drug in the plasma or blood of a patient followingadministration of a dose of the drug or form of drug to the patient.

By definition, when a medication is administered intravenously, itsbioavailability is 100 percent. However, when a medication isadministered via other routes (such as orally), its bioavailabilitydecreases (due to incomplete absorption and first-pass metabolism). Morespecifically, bioavailability is a measure of the ratio of the amount ofdrug “absorbed” from a test formulation to the amount “absorbed” afteradministration of a standard formulation. Frequently, the “standardformulation” used in assessing bioavailability is the aqueous solutionof the drug, given intravenously.

The amount of drug absorbed is taken as a measure of the ability of theformulation to deliver drug to the sites of drug action;obviously—depending on such factors as disintegration and dissolutionproperties of the dosage form, and the rate of biotransformationrelative to the rate of absorption—dosage forms containing identicalamounts of active drug may differ markedly in their abilities to makedrug available, and therefore, in their abilities to permit the drug tomanifest its expected pharmacodynamic and therapeutic properties. The“amount absorbed” is conventionally measured by one of two criteria,either the area under the time-plasma concentration curve (AUC) or thetotal (cumulative) amount of drug excreted in the urine following drugadministration.

A linear relationship exists between the AUC and dose when the fractionof the drug absorbed is independent of dose, and elimination rate(half-life) and volume of distribution are independent of dose anddosage form. However, when AUC is dependent on dose, as occurs when, forexample, there is saturable absorption, significant metabolism, or poorsolubility of the drug in the GI tract, a non-linear relationship existsbetween AUC and dose.

In order to compare the relative bioavailability of various forms ofcreatine and to correct for the slightly different doses of creatineadministered with various forms due to the different molecular weightsof the salt forms, the AUC plasma uptake values observed for creatinemonohydrate and creatine HCl are entered into the following equation toproduce a ratio:

$\frac{\left( {{AUC}_{SampleA}*{Dose}_{B}} \right)}{{AUC}_{SampleB}*{Dose}_{A}}$Based on this relationship, the relative bioavailability of creatine HClto creatine monohydrate is preferably about 1.5 or greater, morepreferably about 1.55 or greater, and even more preferably about 1.65 orgreater. In one embodiment, the ratio is about 1.70 or greater.

In other words, the relative bioavailability of creatine HCl ispreferably about 50 percent greater than creatine monohydrate, morepreferably about 55 percent greater than creatine monohydrate and mostpreferably about 60 percent greater than creatine monohydrate. In oneembodiment, the bioavailability of the creatine HCl is at least about 65percent greater than bioavailability of creatine monohydrate. In anotherembodiment, the creatine HCl has a bioavailability of at least about 70percent greater relative to creatine monohydrate.

Creatine HCl Stability

The half-life of other known forms of creatine in blood plasma is short(approximately 1-1.5 hours). Thus, to be effective, the creatineformulation must be able to reach desired blood plasma levels rapidly.In view of the bioavailability of previously known forms of creatine,such desired blood plasma levels can be obtained only by theadministration of high doses of creatine, e.g., 5 to 10 g for mean bodyweights of about 70 kg.

In contrast, the creatine HCl of the invention is able to obtain highblood plasma levels at low doses at least in part due to its increasedstability. In addition, due to the overall increase in stability, thecreatine HCl of the invention is capable of maintaining a minimalcreatine blood serum level for longer periods of time, thereby enhancingan individual's muscle performance.

With regard to latent product storage, standard shelf-life according tothe FDA is considered to be the time it takes for 10 percent of thestarting material to degrade in a given sample. Creatine monohydratetypically exhibits a shelf-life of about one week when stored in aqueoussolution at room temperature. In contrast, the creatine HCl of thepresent invention possesses a shelf-life of about 45 days or greater inaqueous solution. In one embodiment, the shelf-life of the creatine HClof the invention in aqueous solution is at least about 60 days,preferably at least about 75 days. In another embodiment, the creatineHCl of the invention possesses a shelf-life of about 90 days or greaterin aqueous solution.

As will be understood by those of ordinary skill in the art, highertemperatures accelerate degradation of all forms of creatine, includingthe creatine HCl of the invention. However, when exposed to highertemperatures, creatine monohydrate still degrades at a much higher ratethan creatine HCl. In one embodiment, the shelf life of creatine HCl inaqueous solution at a temperature ranging from about 10 to 20 degrees (°C.) higher than room temperature is at least about 14 days, preferablyat least about 25 days, and more preferably at least about 30 days. Inanother embodiment, the shelf life of the creatine HCl at 50° C. is atleast about 1 day, preferably at least about 2 days, and more preferablyat least about 5 days.

Supplement Forms

Due to its enhanced properties, the effective dose of creatine HCl ismuch less than other forms of creatine. In order to increase muscle massand strength, compositions of creatine monohydrate are generally dosedin an amount from about 5 g to about 10 g per 150 pounds body weight.Contrastingly, in one embodiment of the present invention, the effectivedose may range from about one quarter teaspoon to about one tablespoonper hundred pounds body weight, more preferably between about onequarter teaspoon to about one teaspoon per hundred pounds body weight,and most preferably between about one quarter teaspoon to about one halfteaspoon per hundred pounds body weight.

In this aspect of the invention, the effective dose may range from about500 mg to about 1500 mg per 100 pounds body weight. For example, in oneembodiment, the effective dose may be from about 1500 mg to about 3000mg for a subject that weighs up to 250 pounds. In one embodiment, theeffective dose is from about 2250 mg to about 4500 mg for a subject thatweighs over 250 pounds. In another embodiment, the effective dose isfrom about 750 mg to about 1500 mg per 100 pounds body weight.

In comparison to creatine monohydrate, the effective dose of creatineHCl is at least about 50 percent less than the effective dose ofcreatine monohydrate. In another embodiment, the effective dose ofcreatine HCl is at least about 55 percent less than the effective doseof creatine monohydrate. In yet another embodiment, the effective doseof creatine HCl is at least about 60 percent less, preferably at leastabout 65 percent less, than the effective dose of creatine monohydrate.For example, the effective dose of creatine HCl is preferably about 70percent less than the effective dose of creatine monohydrate.

In one embodiment of the invention, creatine HCl may be provided in aliquid, gel, or powder form, with powders suitable for mixing with wateror other liquids being preferred. These formulations may be added into abeverage. In addition, the creatine HCl may be provided as an ingredientpremixed in a beverage. Examples of beverages contemplated by theinvention include, but are not limited to, sports drinks and liquid mealreplacements.

In addition to the sports beverage area, various other applications foruse with creatine HCl are contemplated by the present invention, and mayinclude its application in functional food supplements, includingso-called “athletic bars” and “sports bars.”

It is contemplated that the creatine HCl may be combined with any or allof the following compounds: proteins, amino acid supplements, complexcarbohydrates, D-Ribose, fats and fiber. Suitable sources of proteins inthe present invention may include proteins derived from milk, wheyprotein, hydrolyzed beef protein, casein and salts thereof. Otherpreferred proteins may include peanut protein, wheat protein, eggprotein, leptin, and vegetable proteins, such as soy protein. Thehydrolyzed beef protein may be bovine bone gelatin.

In various embodiments of the invention, fats may be used to providelong term energy. Fats useful in the present invention may include, butare not limited to, cocoa butter, milk fat, vegetable oil, hydrogenatedvegetable oils, such as hydrogenated palm oil, hydrogenated shea oil,hydrogenated cottonseed oil, hydrogenated coconut oil, hydrogenated cornoil, hydrogenated soybean oil, and hydrogenated peanut oil;caprocaprylbehenin; monounsaturated fats such as olive oil and canolaoil, sunflower and safflower oils; fish and marine fats.

In addition, fats containing linoleic and linoleic esters havenutritionally desirable features and are thus contemplated for inclusionin the composition of the invention. Moreover, polyols, such as sugaralcohols, may be used in the formulation. Non limiting examples ofsuitable polyols for use with the present invention include hydrogenatedisomaltulose, maltitol, sorbitol, lactitol, erythritol, mannitol,xylitol, polydextrols, and mixtures thereof. Glycerin might, undercertain definitions, be included among the polyols, but for the purposeof the present invention, we classify it separately.

Carbohydrates for fast energy for us with the present invention mayinclude, but are not limited to, glucose, fructose, galactose, sucrose,lactose, maltose, ribose, and combinations thereof. Other carbohydratessuitable for use in the invention may include, but are not limited to,starches, glycogen, fibers, cellulose, beta glucan, pectin, guar gum,and mixtures thereof.

Sweeteners and flavoring agents may be added individually or incombination to improve or alter the taste of the creatine HCl formula,functional food supplement, or beverage. Sweeteners appropriate for usein the present invention are preferably, non-nutritive sweeteners, andmay include sucralose, aspartame, saccharin, and acesulfame potassium.Other sweeteners may include neohesperidin dihydrochalcone,glycyrrhizin, thaumatin, alitame, and stevioside. Flavoring agents mayinclude cocoa or yogurt, which may be used in combination with vanillinor vanilla extract. Other preferred flavoring agents may include peanutbutter, mint, cheesecake, hazelnut paste, almonds, granola, coconut,strawberry, banana, cherry, plum, raspberry, lemon, orange, lime,pineapple, blueberry and other fruit flavors, coffee, or cremes andjellies, and combinations thereof.

The present invention is also directed to creatine HCl compositions thatalso contain other forms of creatine, carbonate salts,methylsulfonylmethane, glucosamine (preferably used in the form of thesalt with hydrochloric, sulfuric, phosphoric, or other biocompatibleacid), chondroitin, or combinations thereof. When creatine HCl iscombined with other forms of creatine, it is envisioned that creatineHCl will account for greater than 50 percent of the total creatine inthe composition. Other forms of creatine appropriate for use withcreatine HCl include creatine esters, creatine pyruvate, creatinephosphate, creatine alpha-ketoglutarate, creatine citrate, andcombinations thereof.

The creatine HCl of the present invention can also be used as a feedadditive in livestock to further enhance the energy requirements ofcompanion animals, sporting and gaming animals, livestock, and otheranimals, as may be desired and required. In particular, creatine HCl mayhave immediate applications in the solid oral dosage supplementationarea, as an additive or a feed supplement for such animals. Or, it maybe added into any liquid that is consumed by such animals.

It is contemplated that the oral supplementation of this invention maybe provided in a solid oral dosage form, such as in a capsule form, fortreatment requirements when taken by a human, animal, and the like. Oraldosage forms encompass tablets, dragees, and capsules. In addition, thecreatine HCl may be in a form that can be administered rectally, such asa suppository. Other dosage forms include suitable solutions foradministration topically, parenterally or orally, and compositions whichcan be administered buccally or sublingually.

In one embodiment, the supplement may be a combination of a powder and asolid oral dosage form. In this regard, the amount of creatine HCl inthe supplement is preferably about 500 mg to about 2000 mg (inclusive ofany binders, sugars, fillers or excipients). For example, the supplementmay contain from about 700 mg to about 1500 mg, preferably at leastabout 750 mg (inclusive of any binders, sugars, fillers or excipients).

When the creatine HCl of the invention is in a solid oral dosage form,the tablet, dragee, or capsule may include about 500 mg to about 2000 mgof creatine HCl (inclusive of any binders, sugars, fillers orexcipients). In one embodiment, the solid oral dosage form includes fromabout 750 mg to about 1750 mg (inclusive of any binders, sugars, fillersor excipients). In another embodiment, the solid oral dosage formincludes from about 1000 mg to about 1500 mg (inclusive of any binders,sugars, fillers or excipients). In yet another embodiment, the solidoral dosage form includes at least about 1250 mg creatine HCl (inclusiveof any binders, sugars, fillers or excipients).

In another aspect of the invention, the creatine HCl is combined withanother supplement in a solid oral dosage form. For example, thecreatine HCl may be combined with HMB, L-glutamine, ribose, orcombinations thereof in a solid oral dosage form. In one embodiment, thecreatine HCl is included in a solid oral dosage form that includes atleast one other supplement in an amount of about 100 mg to about 500 mg.In another embodiment, the creatine HCl is included in the solid oraldosage form that includes at least one other supplement in an amount ofabout 150 mg to about 400 mg. In yet another embodiment, the creatineHCl is included in the solid oral dosage form that includes at least oneother supplement in an amount of about 150 mg to about 300 mg. Forexample, the creatine HCl may be included in a solid oral dosage formthat includes at least one other supplement in an amount of about 200mg.

In general, in addition to the active compound, i.e., creatine HCl, thepharmaceutical compositions of this invention may contain suitableexcipients and auxiliaries that facilitate processing of the activecompounds into preparations which can be used pharmaceutically.Nonlimiting examples of suitable excipients include fillers such ascalcium phosphates (e.g., tricalcium phosphate or calcium hydrogenphosphate) and binders such as starch, paste, using, for example, maizestarch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, vegetable cellulose such as methyl cellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose sodiumcarboxymethylcellulose, and hydroxyethyl methyl cellulose, and/orpolyvinyl pyrrolidone.

If desired, disintegrating agents may also be added, such as theabove-mentioned starches as well as carboxymethyl starch, cross-linkedpolyvinyl pyrrolidone, agar, or alginic acid or a salt thereof; such assodium alginate. Flow-regulating agents and lubricants are alsocontemplated for use with the creatine HCl and include, but are notlimited to silica, talc, stearic acid or salts thereof, such asmagnesium stearate or calcium stearate and/or polyethylene glycol.

When a polyethylene glycol (PEG) component is used, the PEG may have anaverage molecular weight of about 1000 to about 9000. Commerciallyavailable forms of such PEGs are available under the tradename Carbowax®PEG 3350, PEG 1450, PEG 4000, PEG 4600, PEG 8000, and PEG 6000.

Dragee cores may be provided with suitable coatings which, if desired,may be resistant to gastric juices. For this purpose, concentrated sugarsolutions may be used, which may optionally contain gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,lacquer solutions and suitable organic solvents or solvent mixtures, andcombinations thereof. In order to produce coatings resistant to gastricjuices, solutions of suitable cellulose preparations such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate,dyestuffs and pigments may be added to the tablet of dragee coatings,for example, for identification or in order to characterize differentcombinations of compound doses.

Furthermore, the composition could be added as a fortification to otherfoods.

Methods of Making

A granular precipitate consisting of the creatine HCl of the inventionin high purity and yield may be formed from the reaction of creatinemonohydrate and a solvent that is infused with HCl. Any solvent thatdissolves the creatine monohydrate and precipitates creatinehydrochloride may be employed. In one embodiment, the solvent employedis an alcohol. For example, the solvent may be ethanol. Other alcoholssuitable for use in the present invention include short chain alcoholsselected from methanol, propanol, butanol, isopropanol, and the like. Inaddition, acetonitrile is contemplated for use as a suitable solvent inthe context of the present invention.

The acid catalyst may be any acid catalyst that can be added to asolvent to produce a solution of dissolved HCl. Other non-limitingexamples of suitable acid catalysts include acyl chlorides having thegeneral structure: R—CO—Cl, where R is an organic radical group. Forexample, other acid catalysts contemplated for use with the presentinvention include acetyl chloride, benzoyl chloride, and(chlorocarbonyl) acetic acid. In addition, phosphorus chlorides, thionylchloride (SOCl₂) are contemplated for use in accordance with the presentinvention. Moreover, the HCl may be generated by the reaction ofsulfuric acid and sodium chloride.

The yield of creatine HCl produced in each reaction can be determined by1H-NMR analysis used for organic chemicals or other standard methodsknown in the art. As known to those of ordinary skill in the art, 1H-NMRuses spectroscopy and nuclear magnetic resonance technology to ascertainthe structure of chemical compounds.

Preparations of the creatine HCl of the present invention are preferablyat least about 80 percent pure, preferably at least about 95 percentpure, more preferably at least about 97 percent pure, and even morepreferably at least about 99 percent pure. For example, a preparation ofcreatine HCl in accordance with the present invention may be about 98 to99 percent pure. The term “pure” as used herein refers to the lack ofimpurities in the preparation. The main impurities typically detected inthe composition are creatine ethyl ester hydrochloride and creatininehydrochloride.

In one embodiment, the creatine HCl of the present invention is made asa super-saturated batch that results in yields at least about 139percent greater than those achieved with described techniques. In orderto produce a super-saturated batch of creatine HCl, a solvent and anacid catalyst are combined in a reactor that is cooled to between about0° C. and about 20° C. Following addition of the acid catalyst, thereactor temperature is allowed to return to approximately 38° C., atwhich time the creatine monohydrate can be added. The optimumtemperature for the reaction is preferably between about 30° C. andabout 40° C., more preferably between about 32° C. and 38° C., and mostpreferably between 35° C. and 37° C. One additional advantage of thesuper saturated batch technique is that it requires much less solventcompared to other techniques.

For example, a super-saturated batch of creatine HCl may include betweenabout 1.0 and about 1.1 mole equivalents of acetyl chloride to creatinemonohydrate, and preferably between 4 and 5 L of solvent, preferablyethanol, per kg of creatine monohydrate used. In one embodiment, thebatch is formed from about 1.0 to about 1.1 mole equivalent creatinemonohydrate and about 1.0 to about 1.1 mole equivalent of acetylchloride dissolved in about 1 ml to about 5 ml ethanol (per gram ofcreatine monohydrate). A preferred example of a super-saturated batch ofcreatine HCl can be made using about 410 L of ethanol, about 27.2 kg ofacetyl chloride, and about 100 kg of creatine monohydrate.

In another embodiment, 1.4 mole equivalents of acetyl chloride aredissolved in ethanol to form the solvent. In fact, above 1.5 andincluding 2.0 mole equivalents acetyl chloride, the process producesless desirable creatine ethyl ester hydrochloride at a sacrifice ofyield for creatine hydrochloride. And, above 2.0 mole equivalents acetylchloride, the process forms creatinine hydrochloride. The amount ofethanol employed may vary between about 6 mL to about 10 mL, preferably10 ml. The temperature of the solution may be raised to between about24° C. to about 50° C., preferably from about 25° C. to about 35° C. Inone embodiment, the temperature of the solution is raised to 25° C. Infact, at temperatures above the preferred range, the process producesthe less desirable creatine ethyl ester hydrochloride and, in excess of50° C., the process produces increased amounts of undesirable creatininehydrochloride. The conditions result in precipitation of a hydrochloridesalt of creatine in granular form in the vessel. After reducing thetemperature and pressure to ambient atmospheric temperature andpressure, the manufacturer may collect the granules of creatine HCl andpackage the granules for consumption by humans or livestock afterfiltering and washing with a solvent such as ethanol. An alternateembodiment of the process uses anhydrous creatine.

In yet another embodiment, a manufacturer may produce creatine HCl bybubbling gaseous hydrochloric acid into diethyl ether solvent. Then,about 0 grams to about 5 grams of creatine monohydrate is stirred intothe solvent at 25° C. for two hours. From the reaction, creatine HClprecipitates. The manufacturer then filters and washes the precipitatewith 50 mL of fresh diethyl ether. Lastly, the precipitate dries at roomtemperature and/or in a heated and/or vacuumed dryer to a crystallineform, white in color and then is packaged for human or livestockconsumption. In using the alternative method, the hydrochloric acid mayhave a range of concentrations so long as the hydrochloric acid exceedsthe molar equivalent of creatine monohydrate.

Starting materials useful for preparing compounds and intermediatesthereof, and/or practicing methods described herein are commerciallyavailable or can be prepared by well-known synthetic methods.

EXAMPLES

The following non-limiting examples are merely illustrative of thepreferred embodiments of the present invention, and are not to beconstrued as limiting the invention, the scope of which is defined bythe appended claims.

Example 1

Creatine monohydrate and the creatine hydrochloride of the presentinvention were assessed for relative solubility, and thusbio-availability. The results are shown in Table 1.

TABLE 1 Creatine Creatine Monohydrate Hydrochloride Solubility (at 0.015g/mL 0.888 g/mL 62° F.) Relative Solubility 1.0 59.2 (compared tocreatine monohydrate)

For the creatine monohydrate sample: 5 grams of creatine monohydratewere added to 100 mL of water at room temperature and stirred for 2minutes. The solution was filtered, and then dried and massed todetermine the amount of sample remaining un-dissolved.

For the creatine hydrochloride sample: 50 grams of creatinehydrochloride were added to 100 mL of water at room temperature andstirred for 2 minutes. At that time, another 40 grams (4 doses of 10 geach) until the water remained cloudy at the end of the 2 minutestirring period. The solution was filtered, and then dried and massed todetermine the amount of sample remaining un-dissolved.

Example 2

The saturated solubilities of creatine HCl and creatine monohydrate wereassessed and appear in Table 2.

TABLE 2 Creatine Hydrochloride Creatine Monohydrate Aqueous Solubility679 ± 18 mg/mL 17.9 ± 0.5 mg/mL Solution pH 0.3 8.6

Standard Solutions and Standard Curve Determination:

100 mL stock standard solutions of creatine monohydrate and creatinehydrochloride were prepared by dissolving 50 mg of the creatinederivative in 100 mL deionized water. Standard solutions of 10, 20, 30,40, 50, and 100 μg/mL were then prepared by diluting volumes of stocksolution with deionized water. Standard curves for each salt weregenerated by measuring the absorbance at 210 nm. A linear regression wasgenerated and equation determined for each creatine salt with R²>0.999in all cases.

Saturation Solubility Determination:

Using preliminary measurements, saturated solutions of creatinemonohydrate and creatine hydrochloride in deionized water weredetermined by adding increasing amounts of each salt to 5 mL of water inscrew-capped glass bottles at 25° C. in a shaking water bath. Aliquots(5 mL) were removed after 1.5 hours, centrifuged at 3900 rpm for 10minutes, 1 mL supernatant was diluted, and assayedspectrophotometrically at 210 nm. The mean+standard deviation of thesaturation solubilities of each salt were calculated from thecorresponding standard curves.

Example 3

The plasma uptake and relative bioavailability of creatine HCl andcreatine monohydrate were assessed. The results appear in Table 3.

TABLE 3 Creatine Hydrochloride Creatine Monohydrate Average AUC 117.482.2 AUC Standard Error of the 10.4 8.9 Mean (SEM)

Bioavailability studies were performed in healthy human volunteers tocompare the amount of creatine absorbed following oral administration ofa 5 gram dose of either creatine monohydrate or creatine HCl. A two-armcross-over experimental design was used in which each subject receivedboth creatine monohydrate and creatine HCl. The order of treatment wasrandomly assigned and there was a 1-week wash out period betweencreatine treatments. Blood samples were taken immediately prior tocreatine monohydrate and creatine HCl ingestion and at various timepoints thereafter (30-120 minutes). Plasma creatine was significantlyelevated following either creatine monohydrate or creatine HCladministration. However, peak creatine plasma concentrations and plasmaarea under the curve (AUC) was significantly greater in the creatine HCltreatment arm.

The relative bioavailability was determined according to FDA standardsfor comparing a drug/nutritional supplement from two differentformulations using the equation: AUC A*dose B/AUC B*dose A. Theresultant relative bioavailability for creatine HC compared to creatinemonohydrate was 1.65 with an SEM value of 0.12. These results suggest anapproximately 50 percent increase in bioavailability for creatine HCl.

Example 4

The stability of the creatine HCl of the invention, as compared tocreatine monohydrate, was tested both at room temperature (about 70°F./21° C.) and at 50° C. (122° F.). FIGS. 1 (linear data) and 2 (logscale) provide the results of this test. Each data point isrepresentative of three different samples. Initially, each samplecontained 1.5 mg/mL of creatine HCl or creatine monohydrate dissolved inaqueous solution. The creatine content of each sample was examined overa 45-day period.

As illustrated in FIGS. 1 and 2, creatine HCl demonstrated significantlygreater stability compared to the creatine monohydrate samples. Forexample, at the end of the 45-day period, the creatine HCl samplecontained approximately 95 percent of the original creatine in theaqueous solution at room temperature. Contrastingly, the creatinemonohydrate sample only contained about 75 percent of the originalcreatine at room temperature after 45 days. For further comparison, thestandard degradation time for creatine ethyl ester in water is less thanone minute.

Heating the solutions resulted in an increased rate of degradation forboth sample groups; however, as shown in FIGS. 1 and 2, even at 50° C.,creatine HCl demonstrated superior stability in an aqueous solutioncompared to creatine monohydrate.

The invention described and claimed herein is not to be limited in scopeby the specific embodiments herein disclosed, since these embodimentsare intended as illustrations of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description. Such modifications are alsointended to fall within the scope of the appended claims. All patentsand patent applications cited in the foregoing text are expresslyincorporate herein by reference in their entirety.

What is claimed is:
 1. An oral supplement comprising: creatine HClhaving an aqueous solubility of at least about 15 times greater thancreatine monohydrate in water at 25° C. after a time period of about 1.5hours.
 2. The oral supplement of claim 1, comprised in a beverage, aliquid meal replacement, a nutritional bar, or a food product.
 3. Theoral supplement of claim 1, comprised in an additive or feed supplementfor livestock.
 4. The oral supplement of claim 1, further comprising: atleast one flavoring agent selected from the group comprising cocoa,yogurt, peanut butter, mint, cheesecake, hazelnut paste, almonds,granola, coconut, strawberry, banana, cherry, plum, raspberry, lemon,orange, lime, pineapple, blueberry and other fruit flavors, coffee, orcremes and jellies, and combinations thereof.
 5. The oral supplement ofclaim 1, further comprising: at least one additional supplement selectedfrom the group comprising carbonate salt, methylsulfonylmethane,glucosamine, and chondroitin.
 6. The oral supplement of claim 1, furthercomprising: at least one compound selected from the group comprisingproteins, amino acid supplements, carbohydrates, D-Ribose, fats, fiberand combinations thereof.
 7. An oral supplement comprising: creatine HClhaving a solubility of at least about 150 mg/mL in water at 25° C. aftera time period of about 1.5 hours.
 8. The oral supplement of claim 7,wherein the creatine HCl is at least 95 percent free of contaminants. 9.The oral supplement of claim 7, comprising greater than about 50 percentof creatine HCl.
 10. The oral supplement of claim 7, comprised in aliquid or feed additive.
 11. The oral supplement of claim 7, comprisedin a pill, capsule, tablet, or liquid.
 12. A supplement comprisinggranules for consumption by an animal, wherein the granules comprisecreatine HCl, wherein the creatine HCl has an aqueous solubility of atleast an order of magnitude higher than the aqueous solubility ofcreatine monohydrate.
 13. The supplement of claim 12, further comprisingat least one additional supplement selected from the group comprisingcarbonate salts, methylsulfonylmethane, glucosamine, and chondroitin.14. The supplement of claim 12, further comprising at least one compoundselected from the group comprising proteins, amino acid supplements,carbohydrates, D-Ribose, fats, fiber and combinations thereof.
 15. Thesupplement of claim 12, further comprising at least one flavoring agent.16. The supplement of claim 12, comprised in an additive or feedsupplement for livestock.
 17. The supplement of claim 12, comprised in abeverage, a liquid meal replacement, a nutritional bar, or a foodproduct.
 18. The supplement of claim 12, wherein the creatine HCl has anaqueous solubility of at least 600 mg/ml in water at 25° C. after a timeperiod of about 1.5 hours.
 19. The supplement of claim 12, wherein thegranules consist essentially of creatine HCl.
 20. The supplement ofclaim 12, wherein the granules are at least 95 percent free ofcontaminants.